Glutamine metabolism in critically ill patients.|
|- candidate number||7929|
|- NTR Number||NTR2285|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||13-apr-2010|
|- Secondary IDs||09/083 MEtC VUmc|
|- Public Title||Glutamine metabolism in critically ill patients.|
|- Scientific Title||The Contribution of glutamine to citrulline and arginine synthesis, when alanyl-glutamine is supplied in an enteral dose of 0.5 g/kg alanyl-glutamine/day, in Critically Ill Patients.|
|- ACRONYM||DIPEP HUMAN ICU|
|- hypothesis||We hypothesize that exogenous, enterally provided glutamine contributes substantially to the de novo synthesis of arginine in critically ill patients.|
|- Healt Condition(s) or Problem(s) studied||Intensive Care (IC) patients, Enteral nutrition, Critically ill, Metabolic route, Glutamine, Citrulline, Arginine, alanyl-glutamine|
|- Inclusion criteria||1. Age: > 18;|
2. BMI >18,5 and < 35;
3. Ability to tolerate enteral nutrition, provided by postpyloric tube, meeting full protein/energy requirements based on indirect calorimetric measurements;
4. Expected ICU or medium care stay of a minimum of 5 days;
5. Any ICU patient who is considered ‘stable’;
6. Hemodynamics: No new vasoactive medication during 24 hrs preceding inclusion, maximum dose of vasoactive medication < 5 ml/h;
7. Respiration: PaO2/FiO2 ratio > 200, PEEP < 15 cm H2O;
8. Having obtained his/her or his/her legal representative’s informed consent.
For group 3:
1. Requiring CVVH;
2. No endstage kidney disease (defined by need for dialysis for longer than 3 months);
3. No persistent acute renal failure (loss) (defined as need for renal replacement therapy for more than 4 weeks).
|- Exclusion criteria||1. Planned admission for recovery after elective surgery;|
3. Liver failure, defined by bilirubin levels > 100 µmol/L;
5. Kidney failure, represented by increase in serum creatinine levels to > 150 umol/l, in the absence of primary underlying renal disease, or oliguria, defined as urine output < 0.5 ml/kg during the previous 4 hours;
6. Urea cycle defects;
7. Chronic corticosteroids use ( > 7.5 mg/ day > 3 weeks);
8. Proven bowel malabsorption possibly interfering with intestinal absorptive function, e.g. celiac disease, crohn’s disease, presence of fistulas, major intestinal malabsorption disorder, or short bowel syndrome;
9. Parenteral feeding;
10. Use of medium chain triglycerides or glutamine/citrulline supplements.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-jul-2010|
|- planned closingdate||31-dec-2011|
|- Target number of participants||25|
|- Interventions||1. Group 1 (control group): 10 patients will receive enteral tube feeding, containing 1.5 g/kg protein/day ( including 0.15 g/kg/day glutamine ) for at least 5 days;|
2. Group 2 (treatment group): 10 patients will receive enteral tube feeding for 5 days + 0.5 g/24hr L-alanyl-L-glutamine containing 1.5 g/kg protein (including 0.475 g/kg/day glutamine ).
Each group will receive stable isotopes of glutamine, citrulline, arginine, phenylalanine and tyrosine on two consecutive days, enterally and intravenously in a randomized cross-over manner.
Within 2 patients the tracer protocol will also be performed on the 6th and 7th day. Feeding will be stopped two hours in advance.
3. Group 3 (acute renal failure (ARF)): 5 patients will receive enetral tube feeding, containing 1.5 g/kg protein/day (including 0.15 g/kg/d glutamine) for at least 5 days.
Patients will receive stable isotopes of glutamine, citrulline, arginine, phenylalanine and tyrosine intravenously.
|- Primary outcome||The whole body rate of appearance of glutamine, citrulline and arginine, as well as the conversion of endogenous and exogenous, enterally supplied glutamine into citrulline and arginine at the whole body level.
|- Secondary outcome||1. First pass effect of the gut will be calculated using the difference between the whole body rate of appearance of the amino acids when the tracers are given intravenously or enterally;|
2. Renal amino acid metabolism will be calculated by comparing the tracer whole body rate of appearance of the amino acids in a group with normal kidney function and a group with ARF.
|- Timepoints||On day 4 and 5 (group 1 and 2 only) after ICU admission, stable isotopes will be given to quantify metabolic routes.|
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||dr. A. Beishuizen|
|- CONTACT for SCIENTIFIC QUERIES|| M.A.R. Vermeulen|
|- Sponsor/Initiator ||VU University Medical Center|
(Source(s) of Monetary or Material Support)
|VU University Medical Center|
|- Brief summary||Rationale:|
Critically ill patients are likely to benefit from additional glutamine. Novak et al. demonstrated in their meta analysis that glutamine administration reduced morbidity and Oudemans-van Straaten showed that the magnitude of glutamine deficiency correlates with ICU mortality. In addition, low arginine and citrulline levels correlate with severity of inflammation in critically ill children. Although arginine administration can be beneficial for some groups of trauma and cancer surgery patients, its action as substrate for nitric oxide synthesis and subsequent hemodynamic instability and oxidative stress, may be responsible for disappointing results when supplied to severe critically ill patients. Since glutamine can generate arginine by the citrulline pathway in the kidney, supplying glutamine potentially may be a more physiologic and safe way to administer arginine in the metabolically stressed ICU patient. Hence, positive effects of glutamine could be partially due to the substrate that glutamine delivers for the synthesis of arginine. However, when the intestinal-renal axis is disturbed by renal failure, glutamine administration might not gain similar effects.
We hypothesize that exogenous, enteral provided glutamine contributes substantially to the de novo synthesis of arginine in critically ill patients, which is of clinical significance. Furthermore we hypothesize that patients suffering from acute renal failure have a lower de novo arginine synthesis.
The objective of this clinical study is: To study whether L-glutamine given enterally as the dipeptide L-alanyl-L-glutamine enhances the de novo arginine synthesis in critically ill patients. Secondary objective is to determine the relative contribution of the splanchnic bed to this metabolic route. Tertiary objective is to study whether patients with acute renal failure metabolize amino acids (including glutamine) differently.
The whole body rate of appearance of glutamine, citrulline and arginine, as well as the conversion of endogenous and exogenous, enteral supplied glutamine into citrulline and arginine at the whole body level.
First pass effect of the gut will be calculated using the difference between the whole body rate of appearance of the amino acids when the tracers are given intravenously or enterally.
Renal metabolism will be calculated by comparing the tracer whole body rate of appearance of the amino acids in a group with normal kidney function and a group with ARF.
This is an randomized, clinical trial with 2 groups of 10 critically ill patients.
Patients are randomly assigned to one of the two groups:
Group 1 (control group): 10 patients receive enteral nutrition in the small intestine.
Group 2 (treatment group): 10 patients receive isonitrogenous enteral nutrition including 0.5 g/kg L-alanyl-L-glutamine/hr (=0.475 g/kg glutamine and 0,165 g/kg/day alanine) in the small intestine.
Group 3 (ARF group): 5 patients receive enteral nutrition in the small intestine.
Number of patients:
n=25 (control: n=10; treatment n=10, ARF n=5).
Description of subjects and main criteria for inclusion:
Critically ill patients, staying one week or longer on the ICU, receiving enteral nutrition by a feeding tube.
Tracers: A primed, continuous infusion of L-[2-15N]glutamine; L-[5-13C-4,4,5,5,2H4]citrulline; L-[ring-2H5] phenylalanine; L-[2H2]tyrosine; L-[ring-2H4]tyrosine; L-[guanidino-15N2]arginine (enteral or parenteral).
Route of administration, duration of protocol and tracer infusion:
Group 1 and group 3 (control group and ARF group): Patients will receive enteral tube feeding, containing 1.5 g/kg protein/day ( including 0.15 g/kg/day glutamine ) for at least 5 days.
Group 2 (treatment group): Patients will receive enteral tube feeding for 5 days + 0.5 g/24hr L-alanyl-L-glutamine containing 1.5 g/kg protein (including 0.475 g/kg/day glutamine).
Both groups: The tracer protocol will be performed on the 4th and 5th day after (after at least 3 days of enteral feeding). In randomized order the tracers will be given enterally or parenterally.
Within 2 of the patients (1 control; 1 intervention), the tracer protocol will additionally be conducted at a third and fourth day (day 6 and 7), in which enteral feeding will be stopped 2 hours in advance to enable postprandial measurements and comparison. Tracers will be given intravenously and enterally alternately.
For group 3, tracers will be given intravenously after a minimum of 3 days of enteral feeding. Tracers will be administered when CVVH filter change is necessary.
|- Main changes (audit trail)||14-Jun-2011: Amendment - NM|
1. A third group has been added;
2. Multicenter trial from yes to no;
3. Closingdate prosponed from 31-Dec-2010 to 31-Dec-2011;
4. Target number of participants upgraded from 20 to 25;
5. Second secondary outcome submitted.
|- RECORD||13-apr-2010 - 14-jun-2011|
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